Alcohol and Potential DNA Damage

A recent study completed by the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge suggests a novel reason for why alcohol consumption increases the risk of cancer. In a study published in Nature on 3 January 2018, the Cancer Research UK-funded experiment found that alcohol consumption causes DNA damage in stem cells. In particular, the DNA of haematopoietic stem cells (blood stem cells) are adversely affected by alcohol consumption.

Previous studies that have investigated the carcinogenic effects of alcohol used cell cultures for their experiments. The experiment conducted by the MRC laboratory adopted a novel approach and exposed live mice instead of cultures to ethanol. After chromosome analysis and DNA sequencing of the mice’s genetic information, the team noticed permanent chromosome alterations in the blood stem cells. In particular, the acetaldehyde produced by the body upon consuming alcohol breaks the double-stranded DNA and causes chromosome rearrangements. These mutations increase the risk of cancer because the stem cells become faulty.

The MRC laboratory experiment also observed the role of the enzyme aldehyde dehydrogenase (ALDH) in the body’s response to alcohol. They noticed that mice lacking a functioning ALDH enzyme had four times as much DNA damage as those who did. This confirms our understanding that ALDH is one way the body mitigates the effects of alcohol; ALDH converts acetaldehyde into acetate, which the body uses as energy.

The insight into ALDH’s function in the body compliments our current understanding of the enzyme. For example, a large portion of South East Asians, who on average have lower alcohol tolerances, lack functional versions of ALDH enzymes. This study may also suggest that, based off of one’s inherited ability to produce ALDH enzymes, some individuals may be more prone to the carcinogenic effects of alcohol than others.

Lastly, the study did recognize that cells have DNA repair systems. However, not everyone carries a seamless DNA repair system, as they can often be lost due to chance mutations. Further, with substantial enough alcohol exposure, these systems may fail (as they did with the mice) and result in DNA damage.

The study did not conclude whether such DNA damage was hereditary, as the lab only looked at blood stem cells. Nevertheless, Cancer Research UK has publicized this study as a compelling reason to control alcohol intake and consume in moderation.

Resources

https://www.nature.com/articles/nature25154

https://www.sciencedaily.com/releases/2018/01/180103132629.htm

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Alan Guth and the Multiverse

Feature Photo: The Atlantic

The content from this article was produced by Mathilde Papillon.

On the evening of January 18, 2018, Alan Guth, a famous American theoretical physicist and cosmologist, visited McGill University to deliver a talk entitled “Inflationary Cosmology: Is our Universe Part of a Multiverse”. Over the course of his career, Guth has won several prestigious awards in physics. He currently works as a professor at MIT, and is recognized as the inventor of the Inflation Theory. Across the scientific community, it is largely agreed that the Inflation Theory is humanity’s best guess to date of how to universe came to be.

The talk took place in McGill University’s biggest Lecture hall: Leacock 132. Notably, the room was packed, and organizers had to send dozens of people home due to a lack of seating space. This talk was part of Anna I. McPherson Lectures in Physics, a series of lectures regarding hot topics in physics that McGill has taken part of for twenty years now.

Guth’s talk addressed three main subjects: The theory of inflation, evidence for such, and the resulting possibility of a multiverse. He began by making the distinction between the conventional Big Bang theory, a concept that only addresses the aftermath of the “bang”, and inflation. Inflation describes what happened during the bang. By the laws of general relativity, gravitational repulsion is theoretically possible. In this, gravity works in an opposite way to what we are all used to.

The Inflation theory states that in the beginning, matter was comprised of tiny patches of negative pressure – on the order of 10E-28 cm large – that continued to exponential expansion. The phenomena is driven by repulsive gravity.

The “second miracle of physics”, and the other main idea that is at the heart of the theory of Inflation, is negative energy. This simply states that there exists negative energy, allowing the total amount of energy in the universe to the 0. All the energy that people are “familiar with”, are counterbalanced by negative energy. It is theorized that in the beginning of time, there was an exponential expansion of both positive and negative energies.

Photo: Mathilde Papillon

Next, Guth presented evidence for inflation. He asked a series of questions that are left unanswered by the conventional Big Bang theory, and proceeded to show how Inflation can resolve or explain these gaps in the knowledge.

1. In a macroscopic sense, why is the universe so uniform? Inflation suggests that the universe is stretched out in each region in order to accommodate specific density.
2. Why is the universe flat? If we define Ω to be the ratio between the universe’s measured mass density and the critical mass density for flatness, we find that Ω is equal to 1 to 16 significant digits. Inflation’s gravitational repulsion drives Ω to 1, making the universe’s mass density closer to the mass density required for flatness.
3. On a small scale, why is the universe so non-uniform? Inflation uses a quantum mechanical approach that is based on probability. Therefore, in the beginning of the universe, there is a very high chance that there were improbably, tiny fluctuations caused by gravity. These regions would be a little more dense, and have a gravitational pull that is a little stronger. This phenomenon is known as quantum fluctuations. There is evidence for quantum fluctuations in the universe’s cosmic radiation background.

After addressing these questions, Guth described the possibility of a multiverse as suggested by inflation. Assuming that inflation is correct, since the universe has started to inflate, it should inflate forever. Physicists have determined that the basis for inflation, the material with negative pressure, has a half-life, and decays. However, the rate of inflation is so high, by the time one half-life has gone by, the remaining half that is still ‘active’ has grown to be beginning than the lost half. Therefore, it is possible for the universe to inflate forever.

In the process of inflation, it is possible for pieces of inflating material to break off, creating “pocket universes” on their own. From this, it is possible that our universe is one of these pockets.

Guth kept the large audience engaged for the hour he spoke for, receiving a few rounds of applause. He closed off his talk with a question period, in which an audience member asked him what his thoughts were on the religious and philosophical beliefs that humanity holds. Guth believes that his work shows us how small and insignificant humanity is, but that humanity is important to ourselves. As such, it is important to keep building a civilization that we wish to keep living in.

A Weekend of Engineering: MEC 2017

The Feature photo was taken from the McGill Engineering Competition Facebook page.

Each year, a handful of McGill engineering students organize the McGill Engineering Competition (MEC): a three-day event open only to students in the Engineering Faculty. The 2017 MEC ran from 24 to 26 November. Over the course of a weekend, participants competed in one of eight categories for the chance to represent McGill at the Quebec Engineering Competition in late January.

The eight competition categories were: Junior Design, Senior Design, Consulting Engineering, Impromptu Debate, Engineering Communication, Innovative Design, Re-Engineering, and Scientific Research Presentation. Some of the categories allowed competitors to prepare beforehand, while others presented challenges to the participants the day of. For example, the Junior Design category challenged competitors to build an environmentally-friendly boat that could hold up to one kilogram without sinking.

Teams presented their projects in front of a volunteer judging panel consisting of company representatives or McGill Alumni. The teams were scored based off of a predefined rubric distributed at the beginning of the competition. The top three teams of each event were announced at the awards ceremony on Sunday evening.

The registration fee for the event was $25 and could be purchased during tabling hours in the McConnell Engineering Building or online. The registration fee also included a T-shirt, lanyard, and complimentary meals for the weekend.

MEC is an annual competition at McGill University, held near the end of the Fall term. For more information, please visit the McGill Engineering Competition Facebook page.

Not Sure About SURE?

McGill’s Summer Undergraduate Research in Engineering (SURE) Award gives undergraduate students a 16-week, full-time internship position at an engineering research lab at McGill. Awarded as a scholarship, recipients receive an endowment valued at a minimum of $5,625 and the opportunity to work at a lab for the summer.

The 2018 SURE Application period opened on 16 January, initiated by an information session held on the same day. This year, the Faculty of Engineering is offering 125 awards: a substantial jump from the 90 offered last year. The decade-old program is funded by the NSERC Undergraduate Summer Research Award Program, the Faculty of Engineering, the Trottier Institute for Sustainable Engineering and Design, and other donors.

Overview

The “summer research traineeships” provide students with exposure to research and the graduate school experience. For the first time ever, SURE will also be recognized with an entry on students’ transcripts.

SURE participants work on one of the many research projects associated with the program. The research projects for 2018 were posted on the Faculty of Engineering website on 16 January. There are projects from the Departments of Architecture, Bioengineering, Chemical Engineering, Civil Engineering, Electrical and Computer Engineering, Mechanical Engineering, Mining and Materials Engineering, and Urban Planning. Each project has an associated professor, and some require a minimum study year.

Application Process

Interested students need to contact the supervising professors of the projects they are interested in, to a maximum of 3 projects. Supervisors must first agree that the student should apply to the project before the student can complete the Online Student Application.

Once the student has filled out the application, they will submit it to their selected supervisor. The deadline to apply is 26 January 2018, and the first round of awards will be announced after 19 February.

If you would like more information about SURE, or to access its application, please visit the Faculty of Engineering’s website here.

Soup and Science: Bringing students close to the research

Feature Photo: From McGill University’s Facebook Page

In the beginning of each semester, the Faculty of Science organizes Soup and Science, a week where professors in different departments discuss their current research. Each day features four or five professors, in fields such as (but definitely not limited to) biochemistry, mathematics, management, psychology, and geography. Each professor is given the opportunity to summarize their research in three minutes.

This is an opportunity for undergraduate students, specifically those in U0 and U1, to understand what “research in a research-intensive university is all about”. Listening to talks on the cutting-edge research conducted at McGill allows students to bridge the link between the foundational information they learn in classes with research and the future of their respective fields.

This semester, Soup and Science is running from January 15 – 19 at 11:30-12:30 every day at the Redpath museum. Students should come early, since spaces fill up quickly.

On Wednesday, January 17^th, Suzanne Fortier, the President of McGill University, was a special guest to this series of mini-talks. The talks opened up with the perspective of a student, followed by five McGill professors, and concluded with a series of questions about the talks. After the presentations, students are offered free soup and sandwiches.

Sasha McDowell (Final year Honours Biology student)

Sasha McDowell is an international student who is strongly interested in understanding more about her field. In her second year at McGill, she began working in a molecular biology laboratory during the school year. After taking BIOL 306, Neural Basis of Behaviour, she found herself so interested in the course topic that she began working in the Watt Lab on a SURE scholarship over the summer. In these sixteen weeks of work, she worked with mice and tested potential therapies of human ataxia diseases. Wanting to gain insight into all the aspects of research, she took a field course where work was conducted Mont. Saint-Hilaire. McDowell described the value she found in discovering all the avenues that research consists of.

Professor Nii Addy (Desautels Faculty of Management)

Professor Nii Addy completed an undergraduate degree in Engineering before beginning his work in Management. His work focuses in the cross-sector partnership between different organizations to solve complex societal problems. He showed the group an example of a complex problem; the increase of obesity rates among US adults from 1990 to 2006. In order to solve this systemic problem, it is important to consider a “multiplicity of perspectives”. He described the impact of minor changes, such as proximity, on major changes, the commonplace of obesity in North America. Professor Addy currently works with a “multidimensional proximity framework” to help solve complex societal issues.

Professor Kevin Manaugh (Dept. of Geography, McGill School of Environment, Associate of the School of Urban Planning)

Professor Manaugh’s work primarily deals with the design of sustainable cities. He showed the group images of cities before city-planning became a profession, in which industry were situated next to homes, child labour was prevalent, and cities were commonly plagued with societal, economic, and environmental problems. Ebenezer Howard blazed the trail for urban planning when wrote a book on the idea of a garden city, where cities were designed with the concept of “separation of uses”. In fact, most of North America has developed around this idea of a garden city. Dr. Manaugh’s work deals with how to best design the urban environment in a way that reduces the environmental impact, increases biodiversity, and includes the voices of marginalized people. In his own words, the vision of his research is to improve human well-being while making cities more resilient, socially inclusive, and having less environmental impact.

Professor Eric McCalla (Dept. of Chemistry)

Dr. McCalla is a new professor at McGill who researches in advanced batteries. He described the usefulness of lithium-ion batteries in our mobile devices and electric vehicles. However, the current state of research has not yet allowed these batteries to be utilized in renewable energy. For this to be done, the lifetime of the batteries need to be increased five fold, and the batteries need a higher energy density. In his lab, Professor McCalla studies the effects of different compositions for the positive electrode, and is hoping to study the possibility of replacing the current, liquid electrolyte, with a more stable solid electrolyte.

Professor Thibault Mesplède (Dept. of Microbiology and Immunology)

Dr. Mesplède’s lab currently study HIV, a virus that is not cured by antiretroviral therapy. He hopes to discover whether viral reservoirs are latent, or persistently replicating in hidden spaces or anatomical sites, much in the way that microbial organisms can be found within the extreme conditions of hot springs or freezing tundra. His lab uses deep sequencing to reconstruct viral evolution and the phylogeny of HIV.

Professor Jackie Vogel (Dept. of Biology, Associate professor in Computer Science)

By training, Dr. Vogel is a chemist and a biologist. However, her lab is truly interdisciplinary, using techniques from mathematics and computer science to mine data from biological systems. She currently focuses on the “gaps of knowledge that are particularly interesting”. More specifically, she wishes to find the mechanism that occurs from prophase to prometaphase in mitosis. Spindle pole bodies need to be perfectly aligned along a certain axis in order to replicate properly. She uses a basic projection from linear algebra to determine whether or not the cells have aligned their spindles. By studying a mutant that fails to do so, she is currently working on quantitatively analyzing and visualizing this step in mitosis.

Research Awareness Day 2017

November 25th, 2017 marked the annual Research Awareness Day (RAD) held by the Biochemistry Undergraduate Society (BUGS). One of the most prominent undergraduate research events of the year with over 80 undergraduate attendees, RAD featured a full day of rapid-fire presentations by 10 different biochemistry professors, lunch, and a poster fair featuring graduate and undergraduate students alike. With the diversity in the research topics of the different professors, there was something for everybody, not just those majoring in biochemistry.

Photo: Esther Nam

Photo: Esther Nam

Photo: Esther Nam

Photo: Esther Nam

Once again, RAD 2017 was a great event to learn more about research, network with profs, and to get excited about science. You definitely do not want to miss out on RAD if you have the chance, but for those that didn’t make it to RAD 2017, here’s a glimpse at what the professors talked about:

Dr. Albert Berghuis

As the chair of the biochemistry department, Dr. Berghuis gave a brief snapshot of biochemistry at McGill, past (biochemistry is one of the oldest departments at McGill!) and present, before presenting his lab and his current research. The Berghuis lab centers around structural biology and drugs: the development of anti-cancer drugs, the identification of fungal drug targets, and various other drug related topics. But no topic is as pressing as the central feature of the Berghuis lab: antibiotic resistance. Taking a structural biology approach, using techniques such as x-ray diffraction, NMR, scattering, and electron microscopy, the lab seeks to use structures of bacterial enzymes that confer antibiotic resistance to develop new, better antibiotics.

Dr. Jose Teodoro

The Teodoro lab is in equal parts biochemistry and virology, as their primary focus is to learn how to kill cancer cells using viruses that only seem to kill cancer cells by honing in on specific cellular features that only cancer cells possess. For example, the chicken anaemia virus, which causes anaemia in chickens, only targets and kills rapidly dividing cells by interacting with the Anaphase Promoting Complex/Cyclosome. While this destroys chicken hematopoietic stem cells, it is fantastic news for cancer biologists since cancer cells also tend to divide rapidly. Furthermore,the chicken anaemia virus is small, and its only function is to target and destroy rapidly dividing cells. The Teodoro lab also works on p53, a very well known gene that encodes a tumour-suppressing transcription factor, and its effects on tumor angiogenesis.

Dr. Ian Watson

The Watson lab focuses on melanocyte biology in melanoma. 50% of melanomas have a hotspot mutation BRAF, and 25% have a hotspot mutation in NRAS, both of which are mitogen-activated protein kinase (MAPK) regulators, and are druggable targets. The goal of the lab is to develop a therapeutic strategy for long-term survival, as many current techniques show initial promise but no increase in the rates of long-term survival. The Watson lab created stable Cas9-encoding mice with which genome manipulation can be easily done, and they also collect samples from patients who underwent checkpoint inhibition therapy, so they have excellent models for melanoma, the poster child for precision therapy of the future.

Dr. Alba Guarné

One of the newest additions to the McGill biochemistry department, hailing from McMaster University, the Guarné lab studies genome stability and DNA-protein interactions. DNA needs to be extremely condensed to fit into the tiny nucleus of the cell. Almost all DNA processes require the DNA to be decondensed. Once this occurs, the DNA is under constant attack by many components of the cell. Over time, this constant attack can lead to significant mutations in the DNA if it weren’t for the DNA repair mechanisms that prevented the accumulation of mutations. One of the projects the Guarné lab is currently undertaking is the analysis of DNA mismatch repair, specifically studying how the mechanism can discern which of the two DNA strands contain the mutation. All this is done through structural biological techniques such as x-ray diffraction and EM microscopy.

Dr. Janusz Rak

The Rak lab, at the Montreal Children’s Hospital, is a cancer and angiogenesis laboratory, asking questions related to the complexities of diseases. One disease the Rak lab studies specifically is glioblastoma, a type of brain cancer that kills nearly 100% of patients due to the tendency for the tumour to hemorrhage in the brain, and its peculiar penchant of forming blood clots elsewhere, such as the leg, demonstrating the interactivity of cancer. The lab is interested in the unconventionally connectivities of cells — one that does not involve neither the neural nor the endocrine system. Glioblastoma cells exemplify this lack of convention as they seem to communicate using extracellular vesicles, which Dr. Rak described as “motherships that can change things in different ways”. Techniques used in Dr. Rak’s lab include atomic force microscopy and liquid biopsy.

Dr. Uri David Akavia

The Akavia lab is interested in metabolism bioinformatics in cancer, conducting computer modelling of the metabolism of the entire cell, specifically in cancer cells. The lab also intentionally changes genes known to be involved in metabolism using Cas9, and observes and models the consequences. (This leads to some pretty wild flow charts). Ultimately, the Akavia lab seeks to examine how cancer metabolism makes the cell resistant to treatment or developing cancer, and to develop treatment options from the results.

Dr. Bhushan Nagar

The Nagar lab uses structural biology techniques, specifically x-ray crystallography, to decipher molecular mechanisms that underlie diseases. The lab has a diverse range of research interests, such as analysis of IFIT proteins, members of the innate immunity which interact with viral RNAs to block their replication; AvrA, a bacterial protein that blocks immune signalling in the host cell to promote successful infection by the bacteria; and lysosomal enzymes, a subset of acid hydrolases whose mutations lead to lysosomal storage diseases. The Nagar lab hopes to use information gleaned through structural analysis to develop better therapeutics, such as drugs and pharmaceutical chaperones, for associated diseases.

Dr. Alain Nepveu

The ultimate goal of the Nepveu lab is to develop a novel cancer treatment by exploiting vulnerabilities of the cell (not JUST rapid divisions, but other characteristics as well), as well as examining base excision repair. The Nepveu lab uses mouse models and a lot of different assays to collect the data. Dr. Nepveu also stressed the importance of starting research early, and that you don’t need to have prior research experience to conduct interesting experiments in the lab — the skills you learn from making pizza at your part-time job can be transferred to running a PCR! But ultimately, you should not be shy to approach professors to ask about getting research experience.

Dr. Jason Young

The Young lab’s primary focus is on chaperones, specifically the Hsp70s and 90s, which anyone can learn about in GREAT detail if they take BIOC 212/ANAT 212 from the man himself, but Dr. Young’s RAD presentation was about how to get involved in research, in which he also stressed that you don’t need research experience to get involved in research at the undergraduate level, and that there are many classes such as the 396s and independent research courses available to students, providing a helpful and resourceful end to the rapid-fire talks.

This month on the PDB: December

Hi everybody! 162 structures were released from November 28^th to December 5^th, ranging from the typical Homo sapiens proteins to the zesty proteins of the Asian rice. Without further ado, let us take some time to peruse this newly released selection of never-before seen macromolecule structures!

1. HSP90 WITH [sic] indazole derivative, by Graedler, U., Amaral, M., & Schuetz, D.. You know how part of what makes the PDB exciting is that the PDB releases never-before-seen-structures? Well this is not one such case, but just like the lysozymes of last week, this title is notable in that it is actually the name of not one, but SIX separate releases for this week. Hsp90 (heat shock protein 90) is a chaperone protein that promotes the proper folding, stabilization, and activation of a client polypeptide in an ATP-dependent manner, commonly as a dimer. In teaching materials, Hsp90 usually looks like some weird ellipses lumped together to form some two-pronged rabbit head-looking thing, but now you can see what it really looks like, in six slightly different conformations! Indazole derivatives are Hsp90 inhibitors, and these monomeric structures of human Hsp90 are each binding a slightly different indazole derivative. Why are they monomeric and what’s with all these different indazole derivatives? Well, the paper hasn’t been published yet so you’ll have to keep on guessing for a while, but until then, you can entertain yourself by looking at the structures. The PDB accession codes are 5LNY, 5LNZ, 5LO0, 5LO1, 5LO5, and 5LO6. The following figure includes an approximate surface density of the protein, which is why it probably looks a little strange. You can see there are slight differences in conformation between the structures, but for the most part they look decently similar.
2. Crystal structure of Os79 from O. sativa in complex with UDP, by Wetterhorn, K.M., Gabardi, K., Michlmayr, H., Malachova, A., Busman, M., McCormick, S.P., Berthiller, F., Adam, G., and Rayment, I. This is actually a generalization of the titles of four different structures, all of Os79 from O. sativa in complex with UDP, with and without different mutations and some with different sugar moieties. Oryza sativa, the humble Asian rice, one of the most essential cereal crops to society, is susceptible to head blight infections caused by fungi in the Fusarium genus that affects many other cereal crops as well. Trichothecene toxins are a family of toxins that are responsible for the virulence of Fusarium head blight, and toxic to humans and livestock as well as plants since it inhibits protein synthesis in the eukaryotic ribosome. Os79 is a UDP-glycosyltransferase: it adds a glycosyl moiety to a substrate using a co-substrate such as a UDP-glucose (a glucose bound to a uridine diphosphate). Glycosylating trichothecenes reduces its bioavailability and toxicity, so it would be super rad to engineer a protein that could easily glycosylate these toxins and prevent humanity from losing a lot of crops, some livestock, and a few humans every year. That’s a lot of lives saved! Os79 seems to be a good candidate for this ^type of protein engineering, but this goal is still in the fledgling stages as there are a lot of different trichothecenes and only one Os79 (Remember that enzyme-substrate specificity which we thought made enzymes so cool? Well now it’s sort of biting us in the butt. Enzymes are still cool though, obviously). The good news is that the group that released these structures also did some structural and activity analyses and determined what parts of the structure controlled its specificity. You can read all about it here: http://pubs.acs.org.proxy3.library.mcgill.ca/doi/pdf/10.1021/acs.biochem.7b01007. The PDB accession codes are 6BK0, 6BK1, 6BK2, and 6BK3.

Someone requested the experimental method metrics of the PDB releases, so here they are: out of 162 structures released this week, 146 were obtained through x-ray diffraction. 4 structures were obtained using cryo-electron microscopy, the up-and-coming technology in the world of structural biology (the 2017 Nobel Prize in Chemistry was awarded to the developers of cryo-EM), a lower number than the usual. This week, there are a whopping 12 structures obtained through solution microscopy. What are these mysterious 12 structures? The 4 cryo-EM structures? The 144 x-ray diffraction structures? (You already saw 2 of them.) Go check them out yourself on this week’s PDB release! You can find it here: https://www.rcsb.org/pdb/results/results.do?tabtoshow=Current&qrid=9D74214C. Happy lurking!